Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Trieste, Via Licio Giorgeri 1, 34127 Trieste, Italy.
Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, 35131 Padova, Italy.
Eur J Med Chem. 2018 Sep 5;157:837-851. doi: 10.1016/j.ejmech.2018.08.042. Epub 2018 Aug 20.
[1,2,4]Triazolo[1,5-c]pyrimidine is a promising platform to develop adenosine receptor antagonists. Here, we tried to investigate the effect of the substituent at the 8 position of [1,2,4]triazolo[1,5-c]pyrimidine derivatives on affinity and selectivity at the human A adenosine receptor subtype. In particular, we have introduced both esters and amides, principally with a benzylic nature. In addition, a small series of 5-substituted [1,2,4]triazolo[1,5-c]pyrimidines was designed in order to complete the structure-activity relationship analysis. Several of these new compounds showed affinity towards human A adenosine receptor in the low nanomolar range, with the most potent derivative of the series bringing a 4-ethylbenzylester at the 8 position (compound 18, hAAR K = 1.21 nM). Docking studies performed on the synthesized compounds inside models of human A, A and A adenosine receptors showed similar binding modes, comparable with the typical crystallographic binding mode of the inverse agonist ZM-241,385.
[1,2,4]三唑并[1,5-c]嘧啶是开发腺苷受体拮抗剂的有前途的平台。在这里，我们试图研究[1,2,4]三唑并[1,5-c]嘧啶衍生物 8 位取代基对人 A 腺苷受体亚型亲和力和选择性的影响。特别是，我们引入了酯和酰胺，主要具有苄基性质。此外，设计了一系列 5-取代的[1,2,4]三唑并[1,5-c]嘧啶，以完成构效关系分析。这些新化合物中的几个对人 A 腺苷受体具有低纳摩尔范围内的亲和力，其中该系列最有效的衍生物在 8 位带有 4-乙基苄酯（化合物 18，hAAR K=1.21 nM）。在人 A、A 和 A 腺苷受体模型中对合成化合物进行的对接研究表明，它们具有相似的结合模式，与反向激动剂 ZM-241385 的典型晶体结合模式相当。
